The beta-amyloid hyp(e)othesis; the saga continues

As Churchill would have said, beta-amyloid is a riddle, wrapped in a mystery, inside an enigma. For years now, the "amyloid hypothesis" has been widely-accepted as somehow being importantly responsible for Alzheimer's disease. A few years back researchers were cheerfully confident that amyloid was to AD what artherosclerotic plagues were to heart disease. Rudolph Tanzi, a Harvard neurologist who is a leading authority on the disease and identified the first AD gene, had this to say in an interview in 2000:

Q. How close are we to an effective treatment for Alzheimer's disease? A. I wouldn't be surprised if five years from now we have a pretty effective drug that can slow the disease down enough so that it will be preventable in those at risk, and significantly slow down the deterioration of people who already have it.

Q. Why do you have such optimism?

A. Because, in 15 years, we've gone from knowing little about what causes this disease to having a pretty concrete idea of which biological pathways and body proteins are involved.

If you compare Alzheimer's to heart disease where cholesterol levels must be lowered, we now have our own cholesterol equivalent, which we call the beta-amyloid. The name of the game in Alzheimer's therapy is lowering the accumulation of beta-amyloid in the brain.

It's ten years later and we are no closer to finding an AD drug. Tanzi's hope was not unwarranted given what we knew about amyloid then. But as the amyloid hypothesis matured, so did our understanding of it. First we discovered that it's not the amyloid aggregates themselves but soluble oligomers that are probably responsible for neuronal toxicity. Now it has been proposed that amyloid could have a protective antimicrobial role (I myself had an evolutionary speculation on this) in which case targeting it could even be dangerous. The fact remains that there is no proof that amyloid causes AD. It certainly seems to be related in an important way and many revealing details about it have been uncovered in the last decade, but the proof of principle has been on an increasingly slippery slope and if anything the picture gets murkier and more fascinating.

An article in the latest issue of C & EN basically says that we are targeting beta-amyloid because at least for now we cannot think of anything better to do. It's true that currently, our best bet at treating AD lies in interfering with amyloid formation. But since amyloid formation has never been shown to be causative for AD, treatments targeted at it are always going to be something of a shot in the dark. The advantage of targeting amyloid formation though, as the article says, is that there are lots of points in the mechanism where one can potentially interfere. Two key enzymes responsible for formation of amyloid are beta and gamma-secretase, which clip the amyloid precursor peptide into apparently toxic fragments. Scores of articles are published every year about new chemical agents targeting these two enzymes, and yet the jungle is thicker than we think.

Gamma-secretase is actually a multiprotein complex whose structure is not known, so finding molecules that inhibit it is like finding a black cat in a dark room. More importantly, it's also involved in a second pathway called the Notch pathway which is critical in cell-signaling. Thus blocking it may lead to one of the classic problems in drug discovery whereby eliminating a harmful function also eliminates a useful one, often fatally. Beta-secretase is much more well-studied and its crystal structure has been solved, but it poses a classic structure-based design conundrum; the enzyme's active pocket is flexible and expansive and can bind many ligands in different subpockets. Thus, developing drugs that block this moving target is admittedly challenging. Throw in the requirements for safety and an ability to cross the blood-brain barrier (BBB), and we have a pickle on our hands that's almost as dense as amyloid plaques.

But the much more serious issue is whether any of these strategies will work at all. If amyloid formation turns out to be a side-show in AD progression, then all these strategies might ultimately come to naught. Unfortunately the data so far is not promising. The last few years have seen a disappointing string of late-stage failures of amyloid blocking molecules and antibodies in clinical trials. In some cases the agents have failed to clear the plaques, but tellingly in others, clearing the plagues did not put the disease in remission. Thus the scores of pharmaceutical companies that have several pipeline dwellers focused toward amyloid may be chasing an imaginary rabbit. There are serious concerns that scientists may have to go back to the drawing board and start all over again. This would be a huge setback.

However, hope need not be completely lost. One of the most reasonable explanations for the failure of these agents is simply that they arrived too late on the scene, when the disease had progressed too far to be defeated. Perhaps these drugs would have helped had they been administered earlier. Even cancers that can be treated if detected early fail to be cured in late stages, and AD should be no different. One of the big problems in the field is that detecting AD early is still a challenge and is being addressed by many promising neural imaging initiatives. Perhaps early and focused administration of these drugs could be successful.

Yet it all hinges on putting all your eggs in the amyloid basket. Another protein implicated in AD is tau, which forms tangles in the brain. But as the article says, targeting tau may be even harder than targeting amyloid since it is ubiquitous. Other processes hypothesized to be important for AD include oxidation and other neurotoxic processes of which amyloid may simply be a side-product. And as I was thinking this morning, perhaps no drug will ever be as effective in treating AD as a balanced lifestyle that includes preventive measures; and this may especially be true if amyloid is a natural part of our body's physiology. But as of now we have to keep on trying, and the amyloid hypotheis, shaky as it is, seems to be our best bet of making a dent into this devastating disease. At the very least it will lead to novel basic insights. Perhaps it's an indication of how primitive our understanding of the disease is that we continue to cling to amyloid. Under the present circumstances it seems to be the best we can do, but as another Churchillian admonition indicated, "it is not enough that we do our best; we must do what's necessary".

2 comments:

As a researcher who has worked full-time on Alzheimer's disease pathogenesis for many years, I believe this essay is well written and accurately summarizes the aspects of the current situation that it addresses. However, there are pertinent omissions related to funding that warrant mention in this context.

One, funding for AD research in real dollars has declined significantly over the past few years, putting many labs into damage-control mode rather than a mode in which pioneering research efforts can be undertaken.

Two, the AD research community is rather intensely politicized, most likely because of the funding limitations. If you question the amyloid hypothesis, or see a reason to venture away from it to answer a question, you will encounter a lot of skepticism from power centers of AD research politics at Harvard, WashU, Penn, UCSF, Buck, and Irvine ... which in turn populate foundations that support research such as the Alz Assn, Am Health Assist Fdn, and the Am Fed Aging Res.

Three, there is an enormous fraction of the funding that is available being directed towards clinical studies and human trials. This would certainly be appropriate at a stage when aspects of pathogenesis are well understood to develop therapies with some rationale behind them. However, that is not the case. Clinical studies are being launched with little or no true insight into pathogenesis, and those running them are simply hoping to get lucky. The cost of one clinical study could support the research efforts of 10 laboraties for 5 years. A better use of funds at this point would be to aim at a detailed understanding of pathogenesis. That understanding may or may not ultimately incorporate the amyloid hypothesis, so we need to distribute the available funds among a broader array of labs and keep an open mind about its strengths and weaknesses.

Thanks very much for the enlightening comments. I was not aware there was a rift in the AD community partly driven by the acceptance or lack thereof of the amyloid hypothesis. I hope the situation does not turn into one like that in string theory, where anyone questioning the status quo apparently has a hard time finding positions or funding. If you have been involved in studying AD pathogenesis for a long time, maybe you can highlight what you think are the most promising non-amyloid approaches currently being discussed.

About Me

“Ashutosh (Ash) Jogalekar is a scientist and science writer based in the San Francisco Bay Area. He has been blogging at the “Curious Wavefunction” blog for more than ten years, and in this capacity has written for several organizations including Nature, Scientific American and the Lindau Meeting of Nobel Laureates. His professional areas of interest include medicinal and computational chemistry. His literary interests specifically lie in the history and philosophy of science.”
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